This invention relates generally to the field of drug delivery and more particularly to methods of transport of agents such as pharmaceutically active agents across tissues, including transport by iontophoresis.
The transport of various agents such as metabolites, drugs and nutrients across tissues is a function primarily of three factors: tissue permeability, the presence or absence of a driving force and the size of the area through which transport occurs. The lack of inherent permeability for many tissues renders it difficult to move agents across a body surface. Permeability in many tissues is low because cell membranes are generally composed of lipid bilayers that are relatively impermeable to ionized and uncharged polar species. For example, transport of agents across skin has proved difficult in part because the outer layer of skin termed the stratum corneum consists of tightly packed cells with intercellular lipids which severely impede passage of substances through this barrier.
Oral administration of drugs remains the most common method of drug delivery because the cells lining the intestine tend to be quite permeable and because oral ingestion is generally accepted by patients. This approach, however, has a variety of shortcomings including degradation of the agent within the gut, the inability to apply a driving force, and local gastrointestinal irritation.
Iontophoresis is an alternative approach that can be utilized to deliver agents across a tissue by the application of an electrical current. In practice, iontophoretic methods generally involve positioning an electrode that includes some type of reservoir or absorbent pad that contains the agent to be transferred on the tissue through which delivery is to occur. Another electrode that typically does not include the agent but contains, or is coated with, a conductive gel is also placed in contact with the tissue to complete the electrical circuit.
Application of a voltage between the two electrodes and across the tissue generates a current that causes the ionized agent to move towards the electrode of opposite charge, thereby driving the agent through the tissue. Neutral agents can also be transported, albeit less effectively than ionized agents, via electroosmosis. lontophoresis induces the formation and/or enlargement of pores within tissues, which in turn increase tissue permeability to ionic and polar agents and drive these agents through such pores. When the tissue is skin, the agent penetrates the stratum corneum and passes into the dermo-epidermal layer. The innermost portion of the dermis is typically referred to as the papillary layer and contains a network of capillaries from the vascular system. This network absorbs the agent and subsequently moves it to the main portion of the circulatory system.
A majority of the iontophoretic methods utilize constant-current DC signals to effectuate transport. There are several problems associated with such methods that have resulted in limited acceptance by clinicians, patients and government regulators. One shortcoming of constant-current DC is that the rate of drug delivery changes with the passage of time, even though a constant current is applied. The inability to provide a constant flux at constant current is possibly due to time-dependent changes in tissue porosity, accompanying changes in pore surface charge density and effective pore size over the course of treatment. Such changes pose significant problems in effectively controlling the transdermal delivery of drugs by iontophoresis. It is generally observed that with constant-current DC methods the transference number (fraction of total current carried by a particular charged species) for the bioactive agent increases with time over the course of a typical iontophoresis procedure. This variability in transference number means that the amount of agent transported across a tissue varies with time and cannot be controlled nor predicted effectively.
Problems in controlling the extent of electroporation with constant-current DC methods also result in high inter-and intra-patient variability. Hence, not only does the amount of agent transported vary as a function of time, there is further day-to-day variation for the same individual, as well as variation from person to person.
Yet another problem is a function of byproducts formed during iontophoresis. With many systems, transport is accompanied by water hydrolysis that causes significant pH shifts in the bulk solution and gas formation at the surface of the electrodes. In particular, protons form at the anode while hydroxide ions form at the cathode. Such pH shifts may result in electrochemical bums that can cause tissue damage. In addition, gas formation interferes with the contact, and hence the electrical conduction between the electrode and tissue surface.
Various strategies have been tested to address these problems, including using different waveforms and pulsed DC signals rather than constant-current signals. It has been suggested that the use of pulsed DC signals should theoretically provide improved performance by allowing skin capacitance to discharge, thereby allowing for more controlled current flow and drug delivery. However, many DC pulsed methods suffer from at least some of the same general problems as the constant-current DC methods.
Illustrative of a general pulsed DC method is U.S. Pat. No. 5,019,034 to Weaver et al. Weaver et al. discuss methods that utilize a series of short DC pulses to induce electroporation, in particular a state referred to as reversible electrical breakdown. Various forces can then be utilized to effectuate transport of an agent across a tissue. Once electroporation is established, the nature of the DC pulses (e.g., pulse duration, shape and frequency) is maintained until transfer is complete. U.S. Pat. No. 5,391,195 to Van Groningen discusses a method that uses a pulsed direct current with a frequency of at least 1 kHz and having a duty cycle of at least 80%. Such a signal is asserted to increase the efficiency of transport. Methods employing DC signals and methods designed to monitor the level of current such that a relatively stable current is applied and are discussed in U.S. Pat. No. 4,931,046 to Newman and U.S. Pat. No. 5,042,975 to Chien et al. Certain DC methods employ a combination of pulsed and continuous electric fields. For example, U.S. Pat. No. 5,968,006 to Hoffman discusses a system in which one electrode assembly is used to generate a pulsed DC signal to induce pores in a patient""s skin. A second electrode assembly generates a low voltage continuous electric field of sufficient magnitude to affect transport of molecules through the electroporated region. Each of the foregoing patents, are limited in that they discuss only the use of direct current to perform iontophoresis. These patents also do not discuss how to maintain a substantially constant electrical state in the electroporated region of the tissue in order to maintain constant transference numbers, and hence constant flux, for the agent(s) being transported.
The iontophoretic literature on balance has taught against the utility of AC signals in conducting iontophoresis. It has been the belief of many of those skilled in the art that an AC signal lacks the necessary driving force to achieve effective iontophoretic transport; instead, the view has been that the driving force of an applied DC signal is required to transport a charged particle. The bidirectional nature of an AC signal, led many to conclude that the use of an AC signal would result in inefficient transport at best, and perhaps no net transfer at all. For example, in U.S. Pat. No. 5,391,195 it is noted that xe2x80x9cthe negative pulse [reverse pulse of an alternating current] would result in an inverse effect to the positive pulse, thereby reducing the efficiency of treatment.xe2x80x9d
Nonetheless, certain investigators have discussed the use of AC signals for specific purposes in conducting iontophoresis. For example, several patents to Sabalis (see, e.g., U.S. Pat. Nos. 5,312,325; 5,328,454; 5,336,168; and 5,372,579) discuss systems in which a current oscillator is utilized to apply periodic electrical variations to the skin of a patient, the goal being to trigger rhythmical variations of the potential and resistance of the skin. Such variations in turn are said to cause electroosmotic streaming of a liquid containing a therapeutic compound into the patient""s circulatory system. This type of delivery is said to be in accord with and reinforce the natural biological rhythms of the patient. U.S. Pat. No. 5,328,453 discusses a system in which the direction of current can periodically be reversed to facilitate transport of a primary drug and a counteractor that inhibits blood clotting and enhances circulatory flow. Reversal of polarity is claimed to be efficacious when the primary drug and counteractor are of opposite charge.
Some methods involve application of a series of waveforms that can include an AC component. U.S. Pat. Nos. 5,135,478 and 5,328,452 to Sabalis, for example, discuss iontophoretic methods that include generating a plurality of waveforms that can be separate or overlapping and that can include an AC signal. The duration, repetition rate, shape and harmonic content of each signal are selected to enhance local blood circulation and impede the process of blood coagulation. U.S. Pat. No. 5,421,817 to Liss et al. discusses the use of complex set of overlapping waveforms that includes a carrier frequency and various modulating frequencies that collectively are said to enhance delivery. While allowing for the inclusion of an AC signal in the set of waveforms, Liss et al. reinforced the view that the use of an AC signal is not preferred, noting that a reversal in polarity will xe2x80x9ctend to reverse or slow the transdermal delivery of the drug.xe2x80x9d
There has also been some discussion in the literature regarding the use of AC signals in iontophoresis to minimize the electrochemical burns that can occur with DC methods (see, e.g., Howard et al., (1995) Arch. Phys. Med. Rehabil. 76:463-466; and U.S. Pat. No. 5,224,927 to Tapper). The use of AC signals to control and reduce drug induced skin irritation after passive or iontophoretic transport of a drug has also been discussed (see, e.g., U.S. Pat. No. 6,018,679 to Dinh), as has the use of AC signals in related methods such as in the treatment of hyperhidrosis (see, e.g., Reinauer, et al. (1993) Br. J Derm. 129:166-169).
However, none of these patents or articles that discuss the use of AC signals fully address the challenge of maintaining a substantially constant electrical state and a substantially constant electroporative state such that transport of an agent across the tissue occurs in a predictable and controlled fashion during the time period for delivery. Nor is there a discussion of methods for reducing intra-and inter-subject variability that plagues many iontophoretic methods.
Methods for delivering different agents across a tissue utilizing an AC signal are provided. The methods can be utilized to deliver a number of different agents such as pharmaceutical agents, metal ions and nutrients. During the delivery process, the AC signal is used to maintain a substantially constant electrical state in a region of the tissue through which delivery occurs, thereby allowing agents to be transported across the tissue in a controlled and predictable manner. The methods have utility in a wide range of applications. For example, certain methods can be utilized in various therapeutic treatments, in detoxification methods, in pain management and dermatological treatments.
Thus, certain methods more specifically involve delivering an agent across a tissue by supplying one or more electrical signals, one of which is an AC signal that is applied to the tissue. The AC signal is then adjusted so as to maintain a substantially constant electrical state within a region of the tissue, wherein maintenance of the substantially constant electrical state facilitates delivery of the agent. The AC signal is typically adjusted to maintain a substantially constant state of electroporation in the region of the tissue throughout the time period in which the agent is delivered. With some methods, the electrical state that is maintained by the AC signal is an electrical conductance or electrical resistance. The AC signal applied to the tissue can have essentially any waveform. The waveform can be symmetric or asymmetric, thus including square, sinusoidal, saw-tooth, triangular and trapezoidal shapes, for example. The frequency of the AC signal tends to be at least about 1 Hz, although in other instances the frequency is within the range of about 1 Hz to about 1 kHz, about 1 kHz to about 10 kHz, or about 10 kHz to about 30 kHz.
Other delivery methods include an optional electrical prepulse applied to the tissue prior to the AC signal to induce electroporation within the region of the tissue through which delivery is to occur. The prepulse can be either an AC signal or a DC signal. The voltage of the prepulse generally is in the range of about 1 to about 90 V, in other instances about 9 to about 30 V, in still other instances about 30 to about 40 V, and in yet other instances about 40 to about 90 V. The actual voltage can be any particular voltage or range of voltages within these ranges.
Delivery of the agent across the tissue can be via passive diffusion through an electroporated region induced by the AC signal. Certain methods, however, utilize an optional DC offset signal applied in combination with the AC signal. The DC offset signal is effective to promote delivery of the agent through the region maintained at a substantially constant electrical state. The DC offset signal is typically applied substantially continuously during delivery of the agent and is of a voltage or current effective to control the rate of delivery. The DC offset signal is usually in the range of about 0.1 to 5 V and about 0.01 to 0.5 mA/cm2, but can include any particular voltage, current or range of voltages or currents within this range. In certain methods, the DC offset signal is applied utilizing two electrodes in contact with the tissue and the direction of current flow of the DC offset signal is periodically reversed between the two electrodes.
Still other methods combine both the prepulse and the DC offset with the AC signal to deliver agents across a tissue. Such methods generally involve applying the electrical prepulse to the tissue prior to the AC signal to induce electroporation within the region. The DC offset signal is also applied to the tissue and is effective to promote delivery of the agent through the region maintained at a substantially constant electrical state by the AC signal.
The methods can be utilized with a variety of different types of tissue, including both animal and plant tissues. The tissues can be part of a body surface or artificial. Usually the tissue is skin or mucosal tissue, particularly human skin or mucosal tissue. A variety of agents can also be delivered, including charged and uncharged agents.